Action Points

Note that this meta-analysis of randomized trials suggested that early methotrexate usage among individuals with undifferentiated arthritis delays, but does not prevent, the development of rheumatoid arthritis.

Be aware that outcome definitions varied across the studies.

Treating early undifferentiated arthritis helped delay progression to rheumatoid arthritis (RA), particularly when the treatment was methotrexate, a systematic review and meta-analysis found.

Among nine studies included in the review, any type of intervention was associated with halving the risk of developing RA by 12 months (OR 0.49, 95% CI 0.26-0.90), according to Maria E. Suarez-Almazor, MD, PhD, of the University of Texas in Houston, and colleagues.

"Considering the high percentage of undifferentiated arthritis patients who eventually develop RA, early treatment with methotrexate might be a reasonable approach, given the large effect size observed," they observed.

Undifferentiated arthritis refers to an arthritic-type condition that does not meet the established criteria for a specific condition. Some cases resolve spontaneously, but an estimated half evolve to RA within a year. "Therefore, treating undifferentiated arthritis before it progresses might be critical," they stated.

Several factors have been linked with progression in undifferentiated arthritis, such as the presence of rheumatoid factor and the HLA-DRB1*04 allele, as well as older age, high disease activity, and positivity for anti-cyclic citrullinated peptide (CCP) antibodies. However, no consensus has emerged on which patients should be treated to help prevent the disease becoming chronic.

To address this question, Suarez-Almazor and colleagues conducted a systematic review and meta-analysis of studies that evaluated the efficacy of treatments in undifferentiated arthritis, identifying eight randomized controlled trials and one open-label trial.

The trials ranged from 12 to 30 months in duration and included 981 participants whose ages ranged from 31 to 58. The proportion of women ranged from 42% to 82%. Endpoints included the development of RA, disease activity scores, and radiographic joint damage.

A total of 85 patients received methotrexate, 28 were given abatacept (Orencia), and 25 were given infliximab (Remicade). In addition, 331 received intramuscular methylprednisolone, 31 were given intra-articular methylprednisolone, and 10 received intra-articular samarium-153 particulate hydroxyapatite, which is used for radiation synovectomy, along with triamcinolone hexacetonide.

Among controls, 422 were given placebo, 46 had no treatment, and three had intra-articular triamcinolone hexacetonide.

In direct comparisons, 19% of patients taking methotrexate had developed RA by 1 year compared with 59% of controls, for an absolute treatment benefit of 41%. However, no statistically significant benefits were seen at 30 months (OR 0.60, 95% CI 0.28-1.3) or 60 months (OR 0.75, 95% CI 0.35-1.6). This suggested "that methotrexate delays the onset of chronic arthritis, but does not entirely prevent it," the authors noted.

There also was a trend for efficacy in RA delay/prevention for treatment with intramuscular methylprednisolone, with 47% of patients receiving the treatment developing RA by 12 months compared with 55% of placebo patients (OR 0.72, 95% CI 0.51-1). However, the effect size was "substantially lower" than with methotrexate, they commented.

The researchers also conducted indirect comparisons to evaluate treatments for RA prevention across trials, and found that significant benefits were seen only for methotrexate (OR 0.16, 95% CI 0.08-0.33) and intramuscular methylprednisolone (OR 0.72, 95% CI 0.53-0.99).

Additional analyses of various secondary outcomes showed improvements in multiple clinical outcomes. For instance, patients treated with methotrexate were less likely to experience radiographic progression by 12 to 18 months compared with controls (OR 2.9, 95% CI 1.2-6.9), and patients treated with infliximab were more likely to achieve 20% and 50% improvements on the criteria of the American College of Rheumatology at 3 months compared with controls (OR 11, 95% CI 2-60.6 and OR 21.2, 95% CI 1.1-420.8, respectively).

Moreover, patients receiving abatacept were more likely than controls to achieve remission as measured by the Disease Activity Score in 28 joints at 6 months (OR 4.6, 95% CI 1.2-17.4), and also to have no tender or swollen joints at that time point (OR 10, 95% CI 2.3-43.7).

A subgroup analysis identified anti-CCP-positive patients as possibly needing special consideration, as 67% of this group progressed to RA despite being treated with methotrexate. This finding, in conjunction with the results of an earlier study, suggests that these patients may have a greater need for intervention to prevent progression, the authors stated.

"Future randomized controlled trials with longer follow-up and stratification of risk factors are needed to identify optimal therapy in this population," they concluded.

Limitations of the analysis included potential differences in definitions of undifferentiated arthritis in the included studies and the small sample sizes in some trials.

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